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[transcript] Serial No.110-87 Ketek Clinical Study Fraud: What did Aventis Know? Hearing Before the Subcommittee on Oversight and Investigations of the Committee on Energy and Commerce. 110th Congress Second Session. 2008-02-13: http://frwebgate.access.gpo.gov/cgi-bin/getdoc.cgi?dbname=110_house_hearings&docid=f:48587.pdf [File size: 5.2M]
Ketek Clinical Study Fraud: What Did Aventis Know? House Committee on Energy and Commerce Subcommittee on Oversight and Investigations. 2009-08-22 (link to archived webcast): http://web.archive.org/web/20100203090025/http://archives.energycommerce.house.gov/cmte_mtgs/110-oi-hrg.021208.Ketek.shtml
Hearing Exhibit Binder: http://web.archive.org/web/20100203145033/http://archives.energycommerce.house.gov/cmte_mtgs/021208.KetekHearing.ExhibitBinder.shtml
OCI Investigative Work Product, Ketek Fact Chronology (red arrows indicate especially interesting entries): http://www.circare.org/foia5/ketek_fact_chronology.pdf Accessed on 2009-08-22 at: http://archives.energycommerce.house.gov/Investigations/KetekExhibitBinder/12001.PDF
FDA Office of Criminal Investigations (OCI) Report of Investigation (Loveland), subject:
Regulatory Background of NDA 21-144; Identifying Falsified Data in Study #3014 and Aventis' statements in defense of its submissions.Accessed on 2009-08-22 at: http://archives.energycommerce.house.gov/Investigations/KetekExhibitBinder/10001.PDFWest RJ. Email to Terry Vermillion re: Ketek. 2003-07-28. Accessed on 2009-08-22 at: http://archives.energycommerce.house.gov/Investigations/KetekExhibitBinder/8001.PDF
From which:
I told them it was my feeling that Aventis knew sites were suspect but they did nothing to prove or refute their suspicions. I told them that it was my opinion that Aventis disregarding (sic) the safety of the patients with hopes that FDA would approve their product. I told them that I know they have a shortage of personnel but I think we have to take the necessary steps in order to protect the consumer. I am not interested in whether or not this drug works or doesn't work. I am only interested in whether or not PIs and Aventis blatantly disregarded the obvious.Senate Finance Committee report to FDA Commissioner von Eschenbach (with attachments). 2006-12-13. Accessed on 2009-08-22 at: http://archives.energycommerce.house.gov/Investigations/KetekExhibitBinder/1001.PDF
Senate Finance Committee report to FDA Commissioner von Eschenbach. 2007-12-19. Accessed on 2009-08-22 at: http://archives.energycommerce.house.gov/Investigations/KetekExhibitBinder/2001.PDF
[Sanofi-Aventis] Summary Table of GCP Issues, subject:
Telithromycin Respiratory Effectiveness Assessment Trial (TREAT) Protocol: HMR3647A/ 3014.Accessed on 2009-08-22 at: http://archives.energycommerce.house.gov/Investigations/KetekExhibitBinder/18001.PDFEmail from Ranjan Khosla, re:
Ketek Adult NDA 21-144: FDA Contact Report, October 24, 2002 — FDA Form 483 for Kirkman-Campbell Site.Accessed on 2009-08-22 at: http://archives.energycommerce.house.gov/Investigations/KetekExhibitBinder/26001.PDFDavid Ross presentation at Joint AIDAC/DSARMAC Meeting, subject: NDA 21-144 (Ketek) Data Integrity Issues. 2006-12-15. Accessed on 2015-10-22 at: http://web.archive.org/web/20100321174906/http://archives.energycommerce.house.gov/Investigations/KetekExhibitBinder/34001.PDF
Aventis Pharma Clinical Study Protocol HMR3647A/ 3014. Accessed on 2009-08-22 at: http://archives.energycommerce.house.gov/Investigations/KetekExhibitBinder/17001.PDF
Agreement for Clinical Services between Aventis Pharmaceuticals and PPD Development, LLC. 2001-11-01. Accessed on 2009-08-22 at: http://archives.energycommerce.house.gov/Investigations/KetekExhibitBinder/35001.PDF
FDA Warning Letter to Sanofi-Aventis U.S. LLC. (CDER) 2007-10-23: http://www.circare.org/fdawls2/sanofiaventis_20071017.pdf
Sanofi-Aventis U.S. LLC. Response to FDA Warning Letter. 2007-11-19: http://www.circare.org/fdawls2/sanofiaventis_wlresponse_20071119.pdf
Serial No. 110-5. The Adequacy of FDA To Assure the Safety of the Nation's Drug Supply. Hearing Before the Subcommittee on Oversight and Investigations of the Committee on Energy and Commerce. 110th Congress First Session. 2007-02-13 and 03-22: http://frwebgate.access.gpo.gov/cgi-bin/getdoc.cgi?dbname=110_house_hearings&docid=f:35502.pdf [File size: 7.4M]
Ketek™ is manufactured by Sanofi-Aventis
PPD, Pharmaceutical Product Development Inc. was the contract research organization (CRO) responsible for some or all of the Ketek™ clinical trials. In particular PPD was responsible for study no. 3014, which was the subject of the Wall Street Journal story (and rejected by FDA for problems with data integrity).
Testimony by Ann Marie Cisneros Before the House Energy and Commerce Committee Subcommittee on Oversight and Investigations. 2007-02-13 (Ms. Cisneros was employed as a senior clinical research associate with PPD and charged with monitoring study no. 3014 and in particular the study site of Anne Kirkman-Campbell M.D.): http://www.circare.org/foia5/cisneros_testimony_20070213.pdf
Goldfarb NM. Red Flags in the Study Office: Ann Marie Cisneros on the Ketek TREAT Study. Journal of Clinical Research Best Practices. 2007;3(8). Accessed on 2007-11-01 at: http://firstclinical.com/journal/2007/0708_Cisneros.pdf
Halt Is Urged for Trials of Antibiotic in Children. Gardiner Harris. The New York Times. 2006-06-08.
URL: http://www.nytimes.com/2006/06/08/science/08drug.html?_r=1&oref=slogin&pagewanted=print (Requires free registration.)
Infected Data Fraud, Errors Taint Key Study Of Widely Used Sanofi Drug. Anna Wilde Mathews. The Wall Street Journal. 2006-05-01.
URL: http://online.wsj.com/article_print/SB114644463095840108.html. (Free until 2006-05-10.)
Reps. Launch Investigation of Popular Anti-biotic, Ketek. Representative Edward J. Markey Press Release. 2006-05-01: http://markey.house.gov/index.php?option=content&task=view&id=1510&Itemid=125
Markey EJ, Waxman HA. Letter to Andrew von Eschebach, Acting Commissioner, U.S. Food and Drug Administration. 2006-05-01: http://markey.house.gov/docs/health/FDA%20Letter%20on%20Ketek.pdf
Markey EJ, Waxman HA. Letter to Andrew von Eschebach, Acting Commissioner, U.S. Food and Drug Administration. Appendix A. 2006-05-01: http://markey.house.gov/docs/health/FDA%20Letter%20on%20Ketek%20Appendix%20A.pdf
Markey EJ, Waxman HA. Letter to Andrew von Eschebach, Acting Commissioner, U.S. Food and Drug Administration. Appendix B. 2006-05-01: http://markey.house.gov/docs/health/FDA%20Letter%20on%20Ketek%20Appendix%20B.pdf
Clay KD, Hanson JS, Pope SD, Rissmiller RW, Purdum PP, Banks PM. Brief Communication: Severe Hepatotoxicity of Telithromycin: Three Case Reports and Literature Review. Ann Intern Med. 2006;144(6):415-420. Accessed on 2006-04-02 at: http://www.annals.org/cgi/content/full/144/6/415
Goldfarb NM. David Ross on the FDA. Journal of Clinical Research Best Practices. 2007;3(11). Accessed on 2007-11-01 at: http://firstclinical.com/journal/2007/0711_Ross.pdf
Disputed study no. 3014 is not reported by Sanofi-Aventis in the PhRMA-sponsored study results database at http://www.clinicalstudyresults.org/home/
Maria Anne Kirkman-Campbell, M.D. [Gadsden, AL]: FDA Notice of Initiation of Disqualification Proceedings and Opportunity to Explain 2006-05-18: http://www.circare.org/fdawls3/kirkman-campbell_20060518.pdf
Maria Anne Kirkman-Campbell, M.D. Alabama State Board of Medical Examiners. Voluntary Surrender. 2004-03-24: http://www.albme.org/Documents/PublicDocs/BME_FILES/md.00015616.pdf
Maria Anne Kirkman-Campbell, M.D. State of Florida Board of Medicine. Final Order. 2005-10-18: http://www.bioethicswatch.org/pd/kirkmancampbell_florder.pdf
Maria Anne Kirkman Campbell, M.D. FDA Notice of Opportunity for Hearing (NOOH) 2007-12-21: http://www.circare.org/fdawls3/kirkman-campbell_20071221.pdf
Maria Anne Kirkman Campbell, M.D. FDA Notice of Disqualification to Receive Investigational New Drugs. 2008-05-08: http://www.circare.org/fdawls3/kirkman-campbell_20080508.pdf
Maria Anne Kirkman Campbell, M.D.; FDA Debarment Order 73FR 51305 2008-09-02: http://www.circare.org/fdawls3/kirkman-campbell_20080902.pdf
Egisto Salerno, M.D. [San Diego, CA] FDA Office of Criminal Investigations (OCI) Report of Investigation (Loveland), subject: Regulatory Background of NDA 21-144; Identifying Falsified Data in Study #3014 and Aventis' statements in defense of its submissions.
pp. 5-7: http://archives.energycommerce.house.gov/Investigations/KetekExhibitBinder/10001.PDF
Before the Division of Medical Quality Medical Board of California Department of Consumer Affairs, State of California, In the Matter of the Petition for the Reinstatement of Revoked Certificate of Egisto Salerno M.D. Decision. 2006-05-11: http://www.bioethicswatch.org/pd/salernodecison_20060511.pdf
Jeffrey McLeod, M.D. [Midlothian, VA]: FDA Notice of Initiation of Disqualification Proceedings and Opportunity to Explain (NIDPOE) 2005-08-24: http://www.circare.org/fdawls3/mcleod_20050824.pdf
Manjeet Kaur Achreja, M.D. [Seagrove, NC]: FDA Notice of Initiation of Disqualification Proceedings and Opportunity to Explain (NIDPOE) 2007-08-29: http://www.circare.org/fdawls3/achreja_20070829.pdf
Nasim Golzar, M.D. [Palos Verdes Peninsula, CA] FDA Warning Letter 2008-02-13: http://www.circare.org/fdawls3/golzar_20080213.pdf
Keith J. Pierce, M.D. [Livonia, MI] FDA Notice of Initiation of Disqualification Proceedings and Opportunity to Explain (NIDPOE) 2010-03-17: http://www.circare.org/fdawls3/pierce_fdanidpoe_20100317.pdf
Ashok Shah, M.D. [Titusville, FL] FDA Warning Letter 2008-03-19 : http://www.circare.org/fdawls3/shah_20080319.pdf
Vincent Robert Sghiatti, M.D. [Marina del Rey, CA]: OCI Investigative Work Product, Ketek Fact Chronology. p. 7, Entry dated 2002-05-24 re: PI Vincent Sghiatti, M.D., refusal to permit monitoring. Accessed on 2009-08-22 at: http://archives.energycommerce.house.gov/Investigations/KetekExhibitBinder/12001.PDF
Medical Board of California Physician Profile. Accessed on 2009-08-22 at: http://www2.dca.ca.gov/pls/wllpub/WLLQRYNA$LCEV2.QueryView?P_LICENSE_NUMBER=42926&P_LTE_ID=790
Vincent Robert Sghiatti M.D. Medical Board of California Citation Order [failure to maintain records open for inspection]. 2007-10-17: http://www.circare.org/pd/sghiatti_20071017.pdf
Andrew W. Garner, M.D. [Glens Falls, NY]: Cisneros A. Email re: Garner. 2002-01-21: http://archives.energycommerce.house.gov/Investigations/KetekExhibitBinder/3001.PDF; FDA Office of Criminal Investigations (OCI) Report of Investigation (Loveland), subject: Regulatory Background of NDA 21-144; Identifying Falsified Data in Study #3014 and Aventis' statements in defense of its submissions.
pp. 5-7: http://archives.energycommerce.house.gov/Investigations/KetekExhibitBinder/10001.PDF
William Terpstra, M.D. [Noblesville, IN]: Cisneros A. Email re: Garner. 2002-01-21: http://archives.energycommerce.house.gov/Investigations/KetekExhibitBinder/3001.PDF; FDA Office of Criminal Investigations (OCI) Report of Investigation (Loveland), subject: Regulatory Background of NDA 21-144; Identifying Falsified Data in Study #3014 and Aventis' statements in defense of its submissions.
pp. 5-7: http://archives.energycommerce.house.gov/Investigations/KetekExhibitBinder/10001.PDF
Carl R. Lang, M.D. [Buffalo Grove, IL]: FDA Office of Criminal Investigations (OCI) Report of Investigation (Loveland), subject: Regulatory Background of NDA 21-144; Identifying Falsified Data in Study #3014 and Aventis' statements in defense of its submissions.
pp. 5-7: http://archives.energycommerce.house.gov/Investigations/KetekExhibitBinder/10001.PDF
Ankur Sarkar, M.D. [El Campo, TX]: FDA Office of Criminal Investigations (OCI) Report of Investigation (Loveland), subject: Regulatory Background of NDA 21-144; Identifying Falsified Data in Study #3014 and Aventis' statements in defense of its submissions.
pp. 5-7: http://archives.energycommerce.house.gov/Investigations/KetekExhibitBinder/10001.PDF
Before the Texas State Board of Medical Examiners in the Matter of the Complaint Against Ankur Sarkar, M.D. Agreed Order 2004-06-04: http://www.circare.org/pd/sarkar_20040604.pdf
Richard Allen Barber, D.O. [Denver, CO]: FDA Office of Criminal Investigations (OCI) Report of Investigation (Loveland), subject: Regulatory Background of NDA 21-144; Identifying Falsified Data in Study #3014 and Aventis' statements in defense of its submissions.
pp. 5-7: http://archives.energycommerce.house.gov/Investigations/KetekExhibitBinder/10001.PDF
Jay C. Franklin, M.D. [Miami, FL]: FDA Office of Criminal Investigations (OCI) Report of Investigation (Loveland), subject: Regulatory Background of NDA 21-144; Identifying Falsified Data in Study #3014 and Aventis' statements in defense of its submissions.
pp. 5-7: http://archives.energycommerce.house.gov/Investigations/KetekExhibitBinder/10001.PDF
Florida Board of Medicine Practitioner Profile. Accessed on 2008-02-25 at: http://tinyurl.com/2obnwb
Marie H. Monticciolo, M.D. [Rocky Hill, CT]: FDA Office of Criminal Investigations (OCI) Report of Investigation (Loveland), subject: Regulatory Background of NDA 21-144; Identifying Falsified Data in Study #3014 and Aventis' statements in defense of its submissions.
pp. 5-7: http://archives.energycommerce.house.gov/Investigations/KetekExhibitBinder/10001.PDF
Samuel Rogers Stone, M.D. [Chester, SC]: FDA Office of Criminal Investigations (OCI) Report of Investigation (Loveland), subject: Regulatory Background of NDA 21-144; Identifying Falsified Data in Study #3014 and Aventis' statements in defense of its submissions.
pp. 5-7: http://archives.energycommerce.house.gov/Investigations/KetekExhibitBinder/10001.PDF
Walter N. Gaman, M.D. [Irving, TX]: FDA Notice of Initiation of Disqualification Proceedings and Opportunity to Explain (NIDPOE) to Walter N. Gaman, M.D. (CDER) 2002-10-23:[unrelated to Ketek™ protocol 3014] http://www.circare.org/fdawls3/gaman_20021023.pdf
Yet to do: James L. Knecht, D.O., Perry, OK; Keith Jeffrey Pierce, M.D., Northville, MI; Richard C. Harker, M.D., Lemoyne, PA. Additional PIs in: http://archives.energycommerce.house.gov/Investigations/KetekExhibitBinder/18001.PDF; http://archives.energycommerce.house.gov/Investigations/KetekExhibitBinder/34001.PDF; http://archives.energycommerce.house.gov/Investigations/KetekExhibitBinder/26001.PDF
FDA Drug Approval Package Ketek (Telithromycin) Tablets. Company: Aventis Pharmaceuticals, Inc. Application No.: 021144. Approval Date: 4/01/2004: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/21-144_Ketek.cfm
Data integrity issues are discussed in: FDA Drug Approval Package Ketek (Telithromycin) Tablets. Administrative Documents Part 1: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/21-144_Ketek_Admindocs_P1.pdf
FDA Drug Information Page Telithromycin (marketed as Ketek) Information. 2006-01-20: http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm107824.htm
FDA refused to approve Ketek™ in April 2001:
FDA Anti-Infective Drugs Advisory Committee Briefing Information. 2001-04-26: http://www.fda.gov/ohrms/dockets/ac/01/briefing/3746b1.htm
FDA Anti-Infective Drugs Advisory Committee Slides. 2001-04-26: http://www.fda.gov/ohrms/dockets/ac/01/slides/3746s1.htm
FDA Anti-Infective Drugs Advisory Committee Questions. 2001-04-26: http://www.fda.gov/ohrms/dockets/ac/01/questions/3746q1.htm
FDA Anti-Infective Drugs Advisory Committee Transcript. 2001-04-26: http://www.fda.gov/ohrms/dockets/ac/01/transcripts/3746t1.html
FDA Anti-Infective Drugs Advisory Committee Index of Meetings (2001). 2001-04-26: http://www.fda.gov/ohrms/dockets/ac/cder01.htm#Anti-Infective
FDA approved Ketek™ in January 2003:
FDA Anti-Infective Drugs Advisory Committee Briefing Information. 2003-01-08: http://www.fda.gov/ohrms/dockets/ac/03/briefing/3919b1.htm
FDA Anti-Infective Drugs Advisory Committee Slides. 2003-01-08: http://www.fda.gov/ohrms/dockets/ac/03/slides/3919s1.htm
FDA Anti-Infective Drugs Advisory Committee Questions. 2003-01-08: http://www.fda.gov/ohrms/dockets/ac/03/questions/3919Q1.htm
FDA Anti-Infective Drugs Advisory Committee Transcript. 2003-01-08: http://www.fda.gov/ohrms/dockets/ac/03/transcripts/3919T1.htm
FDA Anti-Infective Drugs Advisory Committee Index of Meetings (2003): http://www.fda.gov/ohrms/dockets/ac/cder03.html#Anti-Infective
Ketek™ was the subject of a third (and contentious) advisory committee meeting in December 2006. Anti-Infective Drugs Advisory Committee December 14-15, 2006 Joint with Drug Safety and Risk Management Advisory Committee: http://www.fda.gov/ohrms/dockets/ac/cder06.html#AntiInfective
The advisory committee meeting is summarized on pp. 17 ff in this document: FDA Office of Criminal Investigations (OCI) Report of Investigation (Loveland), subject:
Regulatory Background of NDA 21-144; Identifying Falsified Data in Study #3014 and Aventis' statements in defense of its submissions.Accessed on 2009-08-22 at: http://archives.energycommerce.house.gov/Investigations/KetekExhibitBinder/10001.PDF
Ketek™ Trials Enrolling Research Subjects on 2006-04-02 Registered at Clinicaltrials.gov
According to the study registry at Clinicaltrials.gov there were seven clinical trials testing Ketek™ for treatment of a variety of infectious diseases; five were enrolling research subjects in the U.S. One study was suspended and one study was not yet open for enrollment in the U.S. Three of the open studies were enrolling children. Because Sanofi-Aventis is not obligated to register trials through Clinicaltrials.gov unless they're subject to FDA IND regulations additional clinical trials of Ketek™ may be underway. NB: on 2006-06-08 Sanofi-Aventis voluntarily paused enrollment in pediatric trials of Ketek™. (1)
1. Study Title: Study Comparing the Clinical Efficacy and Health Outcomes of Outpatients With Mild to Moderate Community-Acquired Pneumonia (CAP) Treated With Either Telithromycin Once Daily for 7 Days, or Azithromycin Once Daily for 5 Days. Study No. HMR3647A/4027. Sponsor: Sanofi-Aventis. Record Last Updated: 2006-05-03. Available from http://www.clinicaltrials.gov/ct/show/NCT00237445?order=83
2. (Pediatric) Study Title: Multinational, Randomized, Double-Blind, Double-Dummy, Comparative Study to Evaluate the Efficacy and Safety of 5 Days Telithromycin 25mg/Kg Od Versus 5 Days Azithromycin 10 Mg/Kg Od Followed by 5 Mg/Kg Od for 4 Days, in Children With Acute Otitis Media. Study No. HMR3647B/3002. Sponsor: Sanofi-Aventis. Record Last Updated: 2006-04-14. Available from http://www.clinicaltrials.gov/ct/show/NCT00315003?order=220
3. (Pediatric) Study Title: Multinational, Randomized, Double-Blind, Double Dummy, Comparative Study to Evaluate the Efficacy and Safety of 5 Days Telithromycin 25mg/Kg Od Versus 10 Days Penicillin V 13.3 Mg/Kg Tid in Children 6 Months to Less Than 13 Years With Streptococcus Pyogenes Tonsillitis/Pharyngitis. Study No. HMR3647B/3004. Sponsor: Sanofi-Aventis. Record Last Updated: 2006-04-14. Available from http://www.clinicaltrials.gov/ct/show/NCT00315042?order=221
4. (Pediatric) Study Title: Multinational, Randomized, Double Blind, Comparative Study to Evaluate the Efficacy and Safety of 5 Days Telithromycin 800 Mg Od Versus 10 Days Penicillin V 500 Mg Tid in Adolescent and Adult Subjects Equal to or Over 13 Years With Streptococcus Pyogenes Tonsillitis/Pharyngitis. Study No. HMR3647B/3006. Sponsor: Sanofi-Aventis. Record Last Updated: 2006-04-17. Available from http://www.clinicaltrials.gov/ct/show/NCT00315549?order=223
5. Study Title: Influence of Oral Telithromycin Vs. Azithromycin on the Endogenous Microflora in Adults With Acute Sinusitis. Study No. HMR3647A-6045. Sponsors: CPL Associates and Sanofi-Aventis. Record Last Updated: 2006-01-04. Available from http://www.clinicaltrials.gov/ct/show/NCT00245440?order=298
Study No. HMR3647A6004 is suspended:
6. Study Title: Randomized Aseptic Pharmacokinetic Pharmacodynamic Outpatient Registry Trial of Respiratory Tract Infections in Adults (RAPPORT). Sponsors: CPL Associates and Sanofi-Aventis. Record Last Updated: 2006-03-27. Available from http://www.clinicaltrials.gov/ct/show/NCT00245453?order=299
Study No. HMR 3647B/3001 is not yet recruiting subjects in the U.S. as of 2006-5-02:
7. (Pediatric) Study Title: Multinational, Randomized, Double-Blind, Double-Dummy, Comparative Study to Evaluate the Efficacy and Safety of Telithromycin 25 Mg/Kg Given Once Daily for 5 or 10 Days Depending on Age and Previous Treatment History Versus Cefuroxime Axetil 15 Mg/Kg, Given Twice Daily for 10 Days, in Children With Acute Otitis Media. Sponsor: Sanofi-Aventis. Record Last Updated: 2006-04-07. Available from http://www.clinicaltrials.gov/ct/show/NCT00174811?order=69
Study results for Ketek™ listed at Clinicalstudyresults.org: http://tinyurl.com/yhs5e5d
Notes
1. Clinicaltrials.gov accessed on 2006-04-02 at: http://www.clinicaltrials.gov/ct
Last Updated: 2015-10-22
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